Decoding mechanism of action and sensitivity to drug candidates from integrated transcriptome and chromatin state

• DOI: 10.7554/elife.78012
• Publication Date: 2022-08-31T10:00:19Z
• Authors: Caterina Carraro; Lorenzo Bonaguro; Jonas Schulte-Sch...; Arik Horne; Marie Oestreich; Stefanie Warnat-H...; Tim Helbing; Michele De Franco; Kristian Haendler; Sach Mukherjee; Thomas Ulas; Valentina Gandin; Richard Goettlich; Anna C Aschenbrenner; Joachim L Schultze; Barbara Gatto
• Keywords: 0301 basic medicine; QH301-705.5; Science; metabolism [Transposases]; Transposases; sensitivity ML prediction; drug candidate; 03 medical and health sciences; computational biology; human; chromatin accessibility; computational biology; drug candidate; human; mechanism of action; multi-omics; sensitivity ML prediction; systems biology; transcriptome; Precision Medicine; RNA; Transposases; Chromatin; Transcriptome; Biology (General); Precision Medicine; Q; R; systems biology; multi-omics; Chromatin; 3. Good health; chromatin accessibility; Medicine; RNA; Transcriptome; ddc:600; transcriptome; Research Article; Computational and Systems Biology; Human; mechanism of action

Omics-based technologies are driving major advances in precision medicine, but efforts still required to consolidate their use drug discovery. In this work, we exemplify the of multi-omics support development 3-chloropiperidines, a new class candidate anticancer agents. Combined analyses transcriptome and chromatin accessibility elucidated mechanisms underlying sensitivity test Furthermore, implemented versatile strategy for integration RNA- ATAC-seq (Assay Transposase-Accessible Chromatin) data, able accelerate extend standalone distinct omic layers. This platform guided construction perturbation-informed basal signature predicting cancer cell lines’ further direct compound against specific tumor types. Overall, approach offers scalable pipeline early phases discovery, understanding mechanisms, potentially inform positioning therapeutics clinic.